EP3594210B1 - Lubiprostone crystals and methods for preparing the same - Google Patents
Lubiprostone crystals and methods for preparing the same Download PDFInfo
- Publication number
- EP3594210B1 EP3594210B1 EP19185546.9A EP19185546A EP3594210B1 EP 3594210 B1 EP3594210 B1 EP 3594210B1 EP 19185546 A EP19185546 A EP 19185546A EP 3594210 B1 EP3594210 B1 EP 3594210B1
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- EP
- European Patent Office
- Prior art keywords
- lubiprostone
- crystal
- lubiprostone crystal
- pattern
- xylene
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- WGFOBBZOWHGYQH-MXHNKVEKSA-N lubiprostone Chemical compound O1[C@](C(F)(F)CCCC)(O)CC[C@@H]2[C@@H](CCCCCCC(O)=O)C(=O)C[C@H]21 WGFOBBZOWHGYQH-MXHNKVEKSA-N 0.000 title claims description 216
- 229960000345 lubiprostone Drugs 0.000 title claims description 215
- 239000013078 crystal Substances 0.000 title claims description 144
- 238000000034 method Methods 0.000 title claims description 28
- 239000002904 solvent Substances 0.000 claims description 64
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 62
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 57
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 52
- OFBQJSOFQDEBGM-UHFFFAOYSA-N Pentane Chemical compound CCCCC OFBQJSOFQDEBGM-UHFFFAOYSA-N 0.000 claims description 46
- DMEGYFMYUHOHGS-UHFFFAOYSA-N heptamethylene Natural products C1CCCCCC1 DMEGYFMYUHOHGS-UHFFFAOYSA-N 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 42
- DCXYFEDJOCDNAF-REOHCLBHSA-N L-asparagine Chemical compound OC(=O)[C@@H](N)CC(N)=O DCXYFEDJOCDNAF-REOHCLBHSA-N 0.000 claims description 32
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical group CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims description 28
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 claims description 26
- RGSFGYAAUTVSQA-UHFFFAOYSA-N Cyclopentane Chemical compound C1CCCC1 RGSFGYAAUTVSQA-UHFFFAOYSA-N 0.000 claims description 24
- DIOQZVSQGTUSAI-UHFFFAOYSA-N decane Chemical compound CCCCCCCCCC DIOQZVSQGTUSAI-UHFFFAOYSA-N 0.000 claims description 24
- BKIMMITUMNQMOS-UHFFFAOYSA-N nonane Chemical compound CCCCCCCCC BKIMMITUMNQMOS-UHFFFAOYSA-N 0.000 claims description 24
- 239000002244 precipitate Substances 0.000 claims description 24
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 23
- IVSZLXZYQVIEFR-UHFFFAOYSA-N m-xylene Chemical group CC1=CC=CC(C)=C1 IVSZLXZYQVIEFR-UHFFFAOYSA-N 0.000 claims description 22
- 238000005033 Fourier transform infrared spectroscopy Methods 0.000 claims description 17
- 239000012530 fluid Substances 0.000 claims description 16
- 229940078552 o-xylene Drugs 0.000 claims description 14
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 12
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 12
- TVMXDCGIABBOFY-UHFFFAOYSA-N octane Chemical compound CCCCCCCC TVMXDCGIABBOFY-UHFFFAOYSA-N 0.000 claims description 12
- 238000001914 filtration Methods 0.000 claims description 11
- 230000001747 exhibiting effect Effects 0.000 claims description 8
- 238000001757 thermogravimetry curve Methods 0.000 claims description 8
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 claims description 7
- 238000003756 stirring Methods 0.000 claims description 7
- 238000001035 drying Methods 0.000 claims description 6
- 238000001228 spectrum Methods 0.000 claims description 6
- 238000001704 evaporation Methods 0.000 claims description 5
- 239000012456 homogeneous solution Substances 0.000 claims description 3
- 230000008020 evaporation Effects 0.000 claims 1
- 239000012535 impurity Substances 0.000 description 30
- 238000004128 high performance liquid chromatography Methods 0.000 description 16
- 238000001556 precipitation Methods 0.000 description 16
- 238000002360 preparation method Methods 0.000 description 13
- 239000000047 product Substances 0.000 description 13
- 238000004090 dissolution Methods 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 238000002425 crystallisation Methods 0.000 description 11
- 239000000725 suspension Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- IOLCXVTUBQKXJR-UHFFFAOYSA-M potassium bromide Chemical compound [K+].[Br-] IOLCXVTUBQKXJR-UHFFFAOYSA-M 0.000 description 8
- 230000008025 crystallization Effects 0.000 description 7
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 6
- 229940011051 isopropyl acetate Drugs 0.000 description 6
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 238000004458 analytical method Methods 0.000 description 4
- 206010010774 Constipation Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 238000009835 boiling Methods 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 238000001938 differential scanning calorimetry curve Methods 0.000 description 3
- 239000005457 ice water Substances 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- PXHVJJICTQNCMI-UHFFFAOYSA-N Nickel Chemical compound [Ni] PXHVJJICTQNCMI-UHFFFAOYSA-N 0.000 description 2
- 229910052782 aluminium Inorganic materials 0.000 description 2
- XAGFODPZIPBFFR-UHFFFAOYSA-N aluminium Chemical compound [Al] XAGFODPZIPBFFR-UHFFFAOYSA-N 0.000 description 2
- 239000012046 mixed solvent Substances 0.000 description 2
- 230000003287 optical effect Effects 0.000 description 2
- 230000005855 radiation Effects 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BGKHCLZFGPIKKU-UHFFFAOYSA-N (13E,15S)-15-hydroxy-9-oxo-prosta-10,13-dienoic acid Natural products CCCCCC(O)C=CC1C=CC(=O)C1CCCCCCC(O)=O BGKHCLZFGPIKKU-UHFFFAOYSA-N 0.000 description 1
- GMVPRGQOIOIIMI-UHFFFAOYSA-N (8R,11R,12R,13E,15S)-11,15-Dihydroxy-9-oxo-13-prostenoic acid Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CCCCCCC(O)=O GMVPRGQOIOIIMI-UHFFFAOYSA-N 0.000 description 1
- 125000004217 4-methoxybenzyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1OC([H])([H])[H])C([H])([H])* 0.000 description 1
- -1 APO-II Chemical compound 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 208000030053 Opioid-Induced Constipation Diseases 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- MYHXHCUNDDAEOZ-UHFFFAOYSA-N Prostaglandin A&2% Natural products CCCCCC(O)C=CC1C=CC(=O)C1CC=CCCCC(O)=O MYHXHCUNDDAEOZ-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 229960000711 alprostadil Drugs 0.000 description 1
- 229940040386 amitiza Drugs 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000002788 crimping Methods 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940126534 drug product Drugs 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- RDYMFSUJUZBWLH-UHFFFAOYSA-N endosulfan Chemical compound C12COS(=O)OCC2C2(Cl)C(Cl)=C(Cl)C1(Cl)C2(Cl)Cl RDYMFSUJUZBWLH-UHFFFAOYSA-N 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 230000004927 fusion Effects 0.000 description 1
- MNWFXJYAOYHMED-UHFFFAOYSA-N heptanoic acid Chemical compound CCCCCCC(O)=O MNWFXJYAOYHMED-UHFFFAOYSA-N 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 229910052738 indium Inorganic materials 0.000 description 1
- APFVFJFRJDLVQX-UHFFFAOYSA-N indium atom Chemical compound [In] APFVFJFRJDLVQX-UHFFFAOYSA-N 0.000 description 1
- 208000002551 irritable bowel syndrome Diseases 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- 229910052759 nickel Inorganic materials 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BGKHCLZFGPIKKU-LDDQNKHRSA-N prostaglandin A1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1C=CC(=O)[C@@H]1CCCCCCC(O)=O BGKHCLZFGPIKKU-LDDQNKHRSA-N 0.000 description 1
- GMVPRGQOIOIIMI-DWKJAMRDSA-N prostaglandin E1 Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1CCCCCCC(O)=O GMVPRGQOIOIIMI-DWKJAMRDSA-N 0.000 description 1
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 238000010898 silica gel chromatography Methods 0.000 description 1
- 238000003860 storage Methods 0.000 description 1
Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/94—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems condensed with rings other than six-membered or with ring systems containing such rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0004—Crystallisation cooling by heat exchange
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0018—Evaporation of components of the mixture to be separated
- B01D9/0022—Evaporation of components of the mixture to be separated by reducing pressure
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0036—Crystallisation on to a bed of product crystals; Seeding
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/005—Selection of auxiliary, e.g. for control of crystallisation nuclei, of crystal growth, of adherence to walls; Arrangements for introduction thereof
- B01D9/0054—Use of anti-solvent
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D2009/0086—Processes or apparatus therefor
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01D—SEPARATION
- B01D9/00—Crystallisation
- B01D9/0077—Screening for crystallisation conditions or for crystal forms
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Definitions
- the present invention relates to novel Lubiprostone crystals and methods for preparing the same, and particularly relates to high purity Lubiprostone crystals and preparation methods thereof.
- Lubiprostone is an active pharmaceutical ingredient in the drug product Amitiza® for the treatment of diseases such as chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation.
- Lubiprostone is categorized as a more unstable prostaglandin E1, and is easily and rapidly degraded to prostaglandin A1, hereinafter referred to as impurity A, under acid or alkaline conditions or even at room temperature as shown in the following Scheme A:
- Impurity A has been identified as the major degradation products or impurity of Lubiprostone. Although impurity A can be removed by silica gel chromatography, additional impurities A will be regenerated in the purified Lubiprostone solution during the subsequent high-temperature, long-duration concentration process. Given this, it has been noted that the best final purification step for industrial mass production of Lubiprostone is crystallization, which does not require high temperatures or a long-duration concentration process.
- Lubiprostone crystal I a crystalline form of Lubiprostone, hereinafter referred to as Lubiprostone crystal I, which can be obtained using various low boiling point solvent systems, such as ethyl acetate/n-hexane, acetone/n-hexane, dichloromethane/n-hexane, isopropanol/n-hexane, acetone/water, and methanol/water. Solvents with low boiling points have typically been used for crystallization because they are easily removed from the resultant crystals simply by allowing the solvent to evaporate.
- the Lubiprostone crystal I has an X-ray powder diffraction pattern as shown in Fig. 1 and a differential scanning calorimetry pattern comprising an endothermic peak with a peak onset temperature of 59.34°C and a peak maximum of 60.97°C.
- US 2010/056808 discloses a crystalline Lubiprostone, hereinafter referred to as Lubiprostone crystal II, obtained in a solvent system of isopropyl acetate/heptane.
- Lubiprostone crystal II obtained in a solvent system of isopropyl acetate/heptane.
- US 2010/056808 teaches that two crystallographically independent molecules, enantiomorphs, were found by optical microscope in the unit cell of Lubiprostone crystal II.
- US 2010/056808 further discloses that an ideal powder pattern was calculated from the single crystal data; this pattern is shown in Fig. 2 and Fig. 3 of the accompanying drawings. Upon comparison, it is found that the pattern shown in Fig. 3 is consistent with that of Fig. 1 , so the polymorph B of Lubiprostone shown in Fig. 3 (i.e., Fig.
- WO 2011/091513 discloses another crystalline form of Lubiprostone, i.e., APO-II, hereinafter referred to as Lubiprostone crystal III, which has an X-ray powder diffraction diffractogram as shown in Fig. 4 and a differential scanning calorimetry thermogram comprising an endothermic peak with a peak onset temperature of approximately 76°C and a peak maximum of approximately 77°C.
- Lubiprostone crystal IV discloses a further Lubiprostone crystal form, hereinafter referred to as Lubiprostone crystal IV, which has an X-ray powder diffraction pattern as shown in Fig. 5 and a differential scanning calorimetry pattern comprising a peak maximum of 58 ⁇ 2°C.
- the present invention relates, at least in part, to two crystalline forms of Lubiprostone, one form being precipitated from o -xylene or m -xylene and termed Lubiprostone crystal V, and the other form being precipitated from p -xylene and termed Lubiprostone crystal VI, and to methods for preparing the Lubiprostone crystal V and the Lubiprostone crystal VI.
- the present invention provides a method for preparing Lubiprostone crystal V, which comprises dissolving Lubiprostone in a first solvent selected from the group consisting of o -xylene, m -xylene, and a mixture thereof, to form a homogenous solution; lowering the temperature and/or adding to the homogenous solution a second solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof until a phase-separated fluid is formed at the bottom; pipetting out an upper clear solution and collecting the remaining phase-separated fluid; and evaporating off the phase-separated fluid under high vacuum until a precipitate is formed.
- a first solvent selected from the group consisting of o -xylene, m -xylene, and a mixture thereof
- the present invention provides another method for preparing Lubiprostone crystal V, which comprises dissolving Lubiprostone in a third solvent selected from the group consisting of o -xylene, m -xylene, ethyl ether, isopropyl ether, methyl tert-butyl ether, and mixtures thereof to form a homogenous solution; lowering the temperature and/or adding to the homogenous solution a fourth solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof; adding a seed crystal of Lubiprostone crystal V; and stirring until a precipitate is formed.
- a third solvent selected from the group consisting of o -xylene, m -xylene, ethyl ether, isopropyl ether, methyl tert-but
- the present invention provides a Lubiprostone crystal V having a X-ray powder diffraction (XRPD) pattern exhibiting its five strongest characteristic peaks at the following 2 ⁇ reflection angles: 6.5 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.6 ⁇ 0.2°, 18.9 ⁇ 0.2°, and 20.2 ⁇ 0.2°, wherein a half peak width of the characteristic peaks at 2 ⁇ reflection angles is between 0.3° and 2°.
- XRPD X-ray powder diffraction
- the present invention provides a method for preparing Lubiprostone crystal VI, which comprises dissolving Lubiprostone in p -xylene to form a homogenous solution; lowering the temperature and/or adding to the homogenous solution a solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof; and stirring until a precipitate is formed.
- a solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof.
- the present invention provides a Lubiprostone crystal VI having an XRPD pattern exhibiting its five strongest intensity peaks at the following 2 ⁇ reflection angles: 7.5 ⁇ 0.2°, 10.3 ⁇ 0.2°, 13.9 ⁇ 0.2°, 18.7 ⁇ 0.2°, and 21.1 ⁇ 0.2°.
- the present invention provides novel Lubiprostone crystals useful for the production of high-purity Lubiprostone by crystallization.
- the method for preparing Lubiprostone crystal V comprises the steps of:
- the selection of the first solvent is the key to determine whether a crystalline form of Lubiprostone can be obtained and/or what kind of crystalline form of Lubiprostone is obtained.
- the first solvent used to dissolve the crude Lubiprostone is selected from the group consisting of o -xylene, m -xylene, and a mixture thereof, preferably o-xylene.
- the volume of the first solvent ranges from about 0.5 ml to about 10 ml, preferably about 1 ml to about 5 ml, and more preferably about 1.5 ml to about 4 ml, per 1 g of the crude Lubiprostone.
- the crude Lubiprostone can be dissolved in the first solvent at a temperature ranging from about 0°C to about 80°C, preferably from about 20°C to about 70°C, and more preferably from room temperature to about 60°C.
- the second solvent is selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof, and preferably n -pentane, n -hexane, cycloheptane, n -heptane, and mixtures thereof.
- the volume of the second solvent ranges from about 0.5 ml to about 30 ml, preferably about 1 ml to about 15 ml, and more preferably about 2 ml to about 10 ml, per 1 ml of the first solvent.
- the second solvent can be added at a temperature ranging from about -10°C to about 80°C, preferably from about -5°C to about 60°C, and more preferably from about 0°C to about 30°C.
- the temperature of the homogenous solution is lowered to a temperature ranging from about -10°C to about 40°C, preferably from about 0°C to about 30°C, and more preferably from about 10°C to about 25°C.
- the precipitation of the crystal can be performed at a temperature ranging from about -10°C to about 40°C, preferably about 0°C to about 30°C, and more preferably about 10°C to about 25°C.
- the step of evaporating off the phase-separated fluid can be performed under reduced pressure of about 10 -4 Torr to about 25 Torr, preferably about 10 -2 Torr to about 10 Torr, and preferably about 10 -1 Torr to about 1 Torr.
- the aforementioned method can directly produce novel Lubiprostone crystal V, which is essentially a single crystalline form and does not contain any other crystalline forms of Lubiprostone, without the addition of any crystal seeds.
- the Lubiprostone crystal V thereby obtained can be used as crystal seeds for copying Lubiprostone crystal V.
- the present invention provides another process to copy Lubiprostone crystal V, which comprises the steps of:
- the third solvent is selected from the group consisting of o -xylene, m -xylene, ethyl ether, isopropyl ether, methyl tert -butyl ether, and mixtures thereof, preferably isopropyl ether.
- the volume of the third solvent ranges from about 0.5 ml to about 10 ml, preferably about 1 ml to about 5 ml, and more preferably about 1.5 ml to about 4 ml, per 1 g of the crude Lubiprostone.
- the crude Lubiprostone can be dissolved in the third solvent at a temperature ranging from about 0°C to about 80°C, preferably from about 20°C to about 70°C, and more preferably from room temperature to about 60°C.
- the fourth solvent is selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and a mixture thereof, and preferably n -pentane, n -hexane, cycloheptane, n -heptane, and mixtures thereof.
- the volume of the fourth solvent ranges from about 0.5 ml to about 30 ml, preferably about 1 ml to about 15 ml, and more preferably about 2 ml to about 10 ml, per 1 ml of the third solvent.
- the fourth solvent can be added at a temperature ranging from about -50°C to about 80°C, preferably from about -10°C to about 60°C, and more preferably from about 0 to about 30°C.
- the temperature of the homogenous solution is lowered to a temperature ranging from about -30°C to about 40°C, preferably about -10°C to about 30°C, and more preferably about 10°C to about 25°C.
- the precipitation of crystal can be carried out at a temperature ranging from about -10°C to about 40°C, preferably about 0°C to about 30°C, and more preferably about 10°C to about 25°C.
- the step of filtering out the precipitate comprises using the fourth solvent or a mixture of the third solvent and the fourth solvent to wash the precipitate.
- the mixed solvent can contain portions of the third solvent and the fourth solvent in a ratio of about 1:1 to about 1:100, preferably about 1:1 to about 1:10.
- the third solvent is the key to determine whether the Lubiprostone crystal V can be directly copied using a seed of Lubiprostone crystal V.
- the applicant found that when using esters such as isopropyl acetate as the third solvent, Lubiprostone crystal V is rapidly converted into Lubiprostone crystal I; thus, such solvent cannot be used to copy Lubiprostone crystal V. Even using a large amount of Lubiprostone crystal V as seed crystals, it is still impossible to obtain Lubiprostone crystal V.
- Lubiprostone crystal V very stable and highly unlikely to convert to Lubiprostone crystal I.
- high-purity Lubiprostone crystal V can be obtained in the presence of a seed crystal of Lubiprostone crystal V. If a crystal seed of Lubiprostone crystal V is not added, the method only produces either Lubiprostone crystal I or a mixture of Lubiprostone crystal I and Lubiprostone crystal V.
- the resultant Lubiprostone crystal V is essentially free of impurity A.
- the crystallization method effectively removes impurity A from the crude Lubiprostone and the crystal seed of Lubiprostone.
- the Lubiprostone crystal V has an XRPD pattern exhibiting its five strongest characteristic peaks at the following 2 ⁇ reflection angles: 6.5 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.6 ⁇ 0.2°, 18.9 ⁇ 0.2°, and 20.2 ⁇ 0.2°.
- the XRPD pattern further comprises characteristic peaks at the following 2 ⁇ reflection angles: 10.8 ⁇ 0.2°, 14.0 ⁇ 0.2°, 14.8 ⁇ 0.2°, 16.0 ⁇ 0.2°, 17.8 ⁇ 0.2°, 21.0 ⁇ 0.2°, and 21.4 ⁇ 0.2°. More preferably, the XRPD pattern of Lubiprostone crystal V is consistent with Fig. 6 .
- the particular data of Lubiprostone crystal V are shown in Table 1.
- the present invention provides a Lubiprostone crystal V having an XRPD pattern exhibiting its five strongest characteristic peaks at the following 2 ⁇ reflection angles: 6.5 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.6 ⁇ 0.2°, 18.9 ⁇ 0.2°, and 20.2 ⁇ 0.2°, wherein a half peak width of the characteristic peaks at 2 ⁇ reflection angles is between 0.3 and 2°.
- the present invention provides a Lubiprostone crystal V having an XRPD pattern substantially as shown in Fig 6 .
- Lubiprostone crystal V obtained by the method of the present invention is essentially a single crystalline form, and thus does not contain any other crystalline forms, such as Lubiprostone crystal I.
- Lubiprostone crystal I As shown in Fig.6 , there is the only one characteristic peak at the 2 ⁇ reflection angles between 2° and 10°, i.e., at 6.5 ⁇ 0.2°, but not 7.6 ⁇ 0.2° (one characteristic peak of Lubiprostone crystal I).
- the present invention provides a Lubiprostone crystal V having an XRPD pattern exhibiting its five strongest characteristic peaks at the following 2 ⁇ reflection angles: 6.5 ⁇ 0.2°, 13.2 ⁇ 0.2°, 15.6 ⁇ 0.2°, 18.9 ⁇ 0.2°, and 20.2 ⁇ 0.2°, and substantially free of a characteristic peak at 2 ⁇ reflection angle of 7.6 ⁇ 0.2°.
- the term "substantially free of” means that in the XRPD pattern, the peak intensity at 7.6 ⁇ 0.2° is less than 5%, preferably less than 1% of the peak intensity at 6.5 ⁇ 0.2°.
- the present invention provides a Lubiprostone crystal V having a differential scanning calorimetry (DSC) thermogram pattern comprising an endothermic peak with a peak onset temperature of 60.6° ⁇ 1°C and a peak maximum of 64.7 ⁇ 1°C.
- DSC differential scanning calorimetry
- the present invention provides a Lubiprostone crystal V having a DSC thermogram pattern substantially as shown in Fig 7 .
- the present invention provides a Lubiprostone crystal V having a 1% KBr Fourier transform infrared (FTIR) spectrum comprising peaks, in terms of cm -1 , at 3388 ⁇ 4, 2938 ⁇ 4, 2872 ⁇ 4, 1729 ⁇ 4, 1713 ⁇ 4, 1415 ⁇ 4, 1247 ⁇ 4, 1222 ⁇ 4, 1207 ⁇ 4, 1180 ⁇ 4, 1105 ⁇ 4, 1091 ⁇ 4, 1060 ⁇ 4, 1006 ⁇ 4, 987 ⁇ 4, 918 ⁇ 4, 761 ⁇ 4, and 723 ⁇ 4.
- FTIR Fourier transform infrared
- the present invention provides a Lubiprostone crystal V having a 1% KBr FTIR spectrum substantially as shown in Fig. 8 .
- the Lubiprostone crystal V of the present invention contains no more than about 0.3%, preferably no more than about 0.2%, preferably no more than about 0.1% of impurity A, and more preferably contains a non-detectable level of impurity A as determined by HPLC method, the detection limit of HPLC method being more than 0.02%.
- the Lubiprostone crystal V of the present invention shows good stability, with no other crystalline forms or degraded products of impurity A, even after six months of storage at normal temperatures for Lubiprostone (about -20°C).
- the process for preparing Lubiprostone crystal VI comprises the steps of:
- the volume of p -xylene ranges from about 0.5 ml to about 10 ml, preferably about 1 ml to about 5 ml, and preferably about 1.5 ml to about 4 ml, per 1 g of the crude Lubiprostone.
- the crude Lubiprostone can be dissolved in p -xylene at a temperature ranging from about 10°C to about 80°C, preferably from about 20°C to about 70°C, and more preferably from about room temperature to about 60°C.
- the fifth solvent is selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof, and preferably n -pentane, n -hexane, cycloheptane, n -heptane, and mixtures thereof.
- the volume of the fifth solvent ranges from about 0.5 ml to about 30 ml, preferably about 1 ml to about 15 ml, and preferably about 2 ml to about 10 ml, per 1 ml of p -xylene. This solvent can be added at a temperature ranging from about 10°C to about 80°C, preferably from about 15°C to about 60°C, and more preferably from about 20°C to about 50°C.
- the temperature of the homogenous solution is lowered to a temperature ranging from about 0°C to about 40°C, preferably from about 15°C to about 30°C, and more preferably from about 15°C to about 25°C.
- the precipitation of the crystal may be performed at a temperature ranging from about 10°C to about 40°C, preferably about 12°C to about 30°C, and more preferably about 15°C to about 25°C.
- the filtering out of the precipitate comprises using the fifth solvent or a mixture of p -xylene and the fifth solvent to wash the precipitate.
- the quantities of p -xylene and the fifth solvent is in a ratio of about 1:1 to about 1:100, preferably about 1:1 to about 1:10.
- Lubiprostone crystal VI obtained by the aforementioned method of the present invention is essentially a single crystalline form, and contains a lower amount or even is substantially free of impurity A.
- Lubiprostone crystal VI has an XRPD pattern exhibiting its five strongest characteristic peaks at the following 2 ⁇ reflection angles: 7.5 ⁇ 0.2°, 10.3 ⁇ 0.2°, 13.9 ⁇ 0.2°, 18.7 ⁇ 0.2°, and 21.1 ⁇ 0.2°. More preferably, the XRPD pattern of Lubiprostone crystal VI is consistent with Fig. 9 .
- Lubiprostone crystal VI The particular data of Lubiprostone crystal VI are shown in Table 2 Table 2 2 ⁇ angle (°) d value ( ⁇ ) relative intensity (%) 6.2 14.2 19.5 7.5 11.9 66.7 10.3 8.6 100.0 11.2 7.9 11.3 11.8 7.5 10.0 12.5 7.1 20.8 12.9 6.9 13.3 13.9 6.3 64.3 14.8 6.0 29.5 15.3 5.8 25.5 17.0 5.2 27.2 18.7 4.7 84.1 19.3 4.6 46.6 21.1 4.2 67.5 22.3 4.0 41.4 23.1 3.9 29.9 23.8 3.7 29.9 26.2 3.4 20.7 28.9 3.1 21.1 31.4 2.9 22.0 33.5 2.7 17.6 37.9 2.4 18.1 41.1 2.2 17.8 45.0 2.0 12.2 47.3 1.9 10.5
- the present invention provides a Lubiprostone crystal VI having a DSC thermogram pattern comprising an endothermic peak with a peak onset temperature of approximately 47.4 ⁇ 1°C and a peak maximum of approximately 50.7 ⁇ 1°C.
- the present invention provides a Lubiprostone crystal VI having a DSC thermogram pattern substantially as shown in Fig. 10 .
- the Lubiprostone crystal VI of the present invention contains no more than about 0.3%, preferably no more than about 0.2%, preferably no more than about 0.1% of impurity A, and more preferably contains a non-detectable level of impurity A as determined by HPLC method, the detection limit of HPLC method being more than 0.02%.
- X-ray Powder Diffraction (XRPD) Analysis The XRPD patterns were collected on a Bruker D2 PHASER diffractometer with fixed divergence slits and ID LYNXEYE detector. The samples (ca. 100 mg) were flatly placed on a sample holder. The prepared samples were analyzed over a 2 ⁇ range from 5° to 50° with step size of 0.02 degrees and step time of 1 second using CuK ⁇ radiation at a power of 10 mA and 30 kV. The CuK ⁇ radiation was removed by a divergent beam nickel filter.
- DSC Differential Scanning Calorimetry
- FTIR Fourier Transform Infrared
- the crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent to obtain 40 g oily Lubiprostone. HPLC analysis of the product showed that 1.1% impurity A was found.
- Oily Lubiprostone (0.51 g, from Example 1) and p -xylene (1.0 ml) were heated at 40°C for dissolution and then cooled to room temperature.
- a solvent of n -pentane (1.0 ml) was added slowly dropwise and the mixture was stirred in an ice-water bath for 1 hour until solid precipitation occurred.
- the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to give 0.38 g Lubiprostone crystal VI. HPLC analysis of the product showed that no impurity A was found.
- the XRPD and DSC results were as shown in Fig. 9 and Fig. 10 .
- Oily Lubiprostone (0.52 g, from Example 1) and p -xylene (1.3 ml) were heated at 40°C for dissolution and then cooled to room temperature. The mixture was stirred in an ice-water bath for 1 hour until solid precipitation occurred. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to give 0.41 g Lubiprostone crystal VI. HPLC analysis of the product showed that no impurity A was found. The XRPD and DSC results were the same as shown in Fig. 9 and Fig. 10 .
- Oily Lubiprostone (0.50 g, from Example 1) and p -xylene (1.0 ml) were heated at 40°C for dissolution and then cooled to room temperature.
- a solvent of n -pentane (1.0 ml) was added slowly dropwise and the mixture was stirred for 1 hour until solid precipitation occurred. Afterwards, the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to give 0.41 g Lubiprostone crystal VI. HPLC analysis of the product showed that no impurity A was found.
- the XRPD and DSC results were the same as shown in Fig. 9 and Fig. 10 .
- Oily Lubiprostone (0.20 g, from Example 1) and p -xylene (1.0 ml) were heated at 40°C for dissolution and then cooled to room temperature.
- a solvent of n-hexane (1.0 ml) was added slowly dropwise and the mixture was stirred for 1 hour until solid precipitation occurred.
- the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to 0.14 g give Lubiprostone crystal VI. HPLC analysis of the product showed that no impurity A was found.
- the XRPD and DSC results were the same as shown in Fig. 9 and Fig. 10 .
- Oily Lubiprostone (0.20 g, from Example 1) and o-xylene (0.5 ml) were heated at 40°C for dissolution and then cooled to room temperature.
- a solvent of n -pentane (1.0 ml) was added slowly dropwise and the mixture was stirred in ice water bath for 2 hours until a phase-separated fluid formed.
- the phase-separated fluid was then separated and evaporated under vacuum at ambient temperature until solid precipitation occurred.
- the resulting precipitate was washed with 1.0 ml n -pentane, and isolated by filtration and dried under vacuum at ambient temperature to give 0.10 g Lubiprostone crystal V.
- HPLC analysis of the product showed that 0.21% impurity A was found.
- the XRPD, DSC, and FTIR results were as shown in Fig. 6 , Fig. 7 and Fig. 8 .
- Oily Lubiprostone (0.20 g, from Example 1) and o-xylene (0.5 ml) were heated at 40°C for dissolution and then cooled to room temperature.
- a solvent of n -pentane (1.0 ml) was added slowly dropwise and the mixture stirred for 2 hours until a phase-separated fluid formed.
- the phase-separated fluid was then separated and evaporated under vacuum at ambient temperature until solid precipitation occurred.
- the resulting precipitate was washed with 1.0 ml n -pentane, and isolated by filtration and dried under vacuum at ambient temperature to give 0.12 g Lubiprostone.
- the XRPD, DSC, and FTIR results were the same as shown in Fig. 6 , Fig. 7 and Fig. 8 . HPLC analysis of the product showed that 0.18% impurity A was found.
- Oily Lubiprostone (0.20 g, from Example 1) and m -xylene (0.5 ml) were heated at 40°C for dissolution and then cooled to room temperature.
- a solvent of n-heptane (1.0 ml) was added slowly dropwise and stirred for half an hour until a phase-separated fluid formed.
- the phase-separated fluid was then separated and evaporated under vacuum at ambient temperature until solid precipitation occurred.
- the resulting precipitate was washed with 1.0 ml n-heptane, and isolated by filtration and dried under vacuum at ambient temperature to give 0.11 g Lubiprostone.
- the XRPD, DSC, and FTIR results were the same as shown in Fig. 6 , Fig. 7 and Fig. 8 . HPLC analysis of the product showed that 0.1% impurity A was found.
- Oily Lubiprostone (0.50 g, from Example 1) and o-xylene (2.0 ml) were heated at 40°C for dissolution and then cooled to room temperature.
- a solvent of n -pentane (4.0 ml) was added slowly dropwise, and then seed crystal (10 mg, crystal V as prepared in Example 6) was added and the mixture was stirred for 1 hour until solid precipitation occurred.
- the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to give Lubiprostone Crystal V (0.32 g).
- the XRPD, DSC, and FTIR results were the same as shown in Fig. 6 , Fig. 7 and Fig. 8 . HPLC analysis of the product showed that no impurity A was found.
- Oily Lubiprostone (0.20 g, from Example 1) and isopropyl ether (0.6 ml) were heated at 40°C for dissolution and then cooled to room temperature.
- a solvent of n-heptane (0.6 ml) was added slowly dropwise, and then seed crystal (10 mg, crystal V as prepared in Example 6) was added and the mixture was stirred for 1 hour until solid precipitation occurred.
- the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for half an hour to give Lubiprostone crystal V (0.11 g).
- the XRPD, DSC, and FTIR results were the same as shown in Fig. 6 , Fig. 7 and Fig. 8 . HPLC analysis of the product showed that no impurity A was found.
- Oily Lubiprostone (0.20 g, from Example 1) and methyl tert-butyl ether (0.6 ml) were heated at 40°C for dissolution and then cooled to room temperature.
- a solvent of n -pentane (0.6 ml) was added slowly dropwise, and then seed crystal (10 mg, crystal V as prepared in Example 6) was added and the mixture was stirred for 1 hour until solid precipitation occurred.
- the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for half an hour to give Lubiprostone crystal V (0.10 g).
- the XRPD, DSC, and FTIR results were the same as shown in Fig. 6 , Fig. 7 and Fig. 8 . HPLC analysis of the product showed that no impurity A was found.
- Oily Lubiprostone (0.20 g, from Example 1) and ethyl ether (0.6 ml) were heated at 40°C for dissolution and then cooled to room temperature.
- a solvent of n -hexane (0.8 ml) was added slowly dropwise, and then seed crystal (10 mg, crystal V as prepared in Example 6) was added and the mixture was stirred for 1 hour until solid precipitation occurred.
- the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for half an hour to give Lubiprostone crystal V (0.14 g).
- the XRPD, DSC, and FTIR results were the same as shown in Fig. 6 , Fig. 7 and Fig. 8 . HPLC analysis of the product showed that no impurity A was found.
- Oily Lubiprostone (0.20 g, from Example 1, enantiomeric purity > 99%) and isopropyl acetate (0.16 ml, 0.8 parts) were heated at 40°C for dissolution and then cooled to 30°C, 25°C, 20°C, 10°C, and 0°C, respectively.
- Heptane (0.84 ml, 4.2 parts) was added slowly dropwise, and the mixture was stirred (at 50, 100, 200, or 250 rpm) for 18 hours until solid precipitation occurred at 30°C, 25°C, 20°C, 10°C, and 0°C, respectively.
- the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature to give Lubiprostone crystal II.
- the XRPD results are shown in Figs. 11(a) to 11(h).
- Figs. 11(a) to 11(h) only the patterns depicted in Fig. 1 and Fig. 3 (Lubiprostone crystal I), but not the pattern depicted in Fig. 2 , can be seen in the XRPD patterns of Figs. 11(a) to 11(h) .
- the results demonstrate that Fig. 1 and Fig. 3 (i.e., Fig. 3 of US 2010/056808 ) show the XRPD patterns of the crystalline forms of Lubiprostone, and Fig. 2 (i.e., Fig. 2 of US 2010/056808 ) shows the XRPD pattern of an enantiomorph of Lubiprostone.
- the XRPD pattern of Lubiprostone crystal V shown in Fig. 6 is similar to that in Fig. 2
- the polymorph A shown in Fig. 2 of US 2010/056808 is an enantiomorph of Lubiprostone, rather than Lubiprostone crystal V which is a single crystalline form.
- a major difference between the patterns shown in Fig. 2 and Fig. 6 is the half peak width of the characteristic peaks at 2 ⁇ reflection angles.
- the half peak width of Lubiprostone crystal V at 2 ⁇ reflection angles is between about 0.3° and about 2°, but the half peak width shown in Fig. 2 at 2 ⁇ reflection angles is below 0.3°, which means that the average crystal sizes of the Lubiprostone crystal V and the enantiomorph of Lubiprostone are different.
- Lubiprostone crystal V (0.20 g, from Example 9) was added to a mixture of isopropyl acetate (0.16 ml) and heptane (0.84 ml)(i.e., the solvent system for crystallization of US 2010/056808 ), and the mixture was stirred at 20°C for 2 hours. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature to give Lubiprostone crystal I. The XRPD results are shown in Figs. 12(a) and 12(b) .
- Lubiprostone crystal V As shown in Figs. 12(a) and 12(b) , the crystalline form of Lubiprostone crystal V has been completely converted to the crystalline form shown in Fig. 1 and Fig. 3 (Lubiprostone crystal I) within only two hours.
- the results prove that Lubiprostone crystal II obtained from US 2010/056808 does not contain any Lubiprostone crystal V because Lubiprostone crystal V cannot be present under the crystallization conditions of US 2010/056808 over 18 hours. Therefore, the Lubiprostone crystal V is a novel crystalline form of Lubiprostone, and the crystalline form shown in Fig. 2 found in the unit cell of Lubiprostone crystal II by optical microscope is an enantiomorph of Lubiprostone, rather than Lubiprostone crystal V.
Description
- The present invention relates to novel Lubiprostone crystals and methods for preparing the same, and particularly relates to high purity Lubiprostone crystals and preparation methods thereof.
- Lubiprostone is an active pharmaceutical ingredient in the drug product Amitiza® for the treatment of diseases such as chronic idiopathic constipation, predominantly irritable bowel syndrome-associated constipation in women and opioid-induced constipation. Lubiprostone is categorized as a more unstable prostaglandin E1, and is easily and rapidly degraded to prostaglandin A1, hereinafter referred to as impurity A, under acid or alkaline conditions or even at room temperature as shown in the following Scheme A:
- Therefore, both the preparation method and the purification process of Lubiprostone generate a certain amount of impurity A as shown in Scheme A. Impurity A has been identified as the major degradation products or impurity of Lubiprostone. Although impurity A can be removed by silica gel chromatography, additional impurities A will be regenerated in the purified Lubiprostone solution during the subsequent high-temperature, long-duration concentration process. Given this, it has been noted that the best final purification step for industrial mass production of Lubiprostone is crystallization, which does not require high temperatures or a long-duration concentration process.
- Many prior art references show crystallization methods for Lubiprostone, but none discloses amounts of impurity A either before or after crystallization. The prior art references focus on the types of crystalline forms of Lubiprostone. Thus, the benefits of conventional crystallization methods for purifying Lubiprostone cannot be evaluated based on the prior art references.
- For example,
WO 2009/121228 discloses a crystalline form of Lubiprostone, hereinafter referred to as Lubiprostone crystal I, which can be obtained using various low boiling point solvent systems, such as ethyl acetate/n-hexane, acetone/n-hexane, dichloromethane/n-hexane, isopropanol/n-hexane, acetone/water, and methanol/water. Solvents with low boiling points have typically been used for crystallization because they are easily removed from the resultant crystals simply by allowing the solvent to evaporate. The Lubiprostone crystal I has an X-ray powder diffraction pattern as shown inFig. 1 and a differential scanning calorimetry pattern comprising an endothermic peak with a peak onset temperature of 59.34°C and a peak maximum of 60.97°C. -
US 2010/056808 discloses a crystalline Lubiprostone, hereinafter referred to as Lubiprostone crystal II, obtained in a solvent system of isopropyl acetate/heptane.US 2010/056808 teaches that two crystallographically independent molecules, enantiomorphs, were found by optical microscope in the unit cell of Lubiprostone crystal II.US 2010/056808 further discloses that an ideal powder pattern was calculated from the single crystal data; this pattern is shown inFig. 2 and Fig. 3 of the accompanying drawings. Upon comparison, it is found that the pattern shown inFig. 3 is consistent with that ofFig. 1 , so the polymorph B of Lubiprostone shown inFig. 3 (i.e.,Fig. 3 ofUS 2010/056808 ) might be the same as Lubiprostone crystal I. However,US 2010/056808 does not directly illustrate the X-ray powder diffraction spectrum of Lubiprostone crystal II. Moreover,US 2010/056808 neither teaches the amount ratios of the two enantiomorphs, nor indicates which enantiomorph is the crystalline form of Lubiprostone. -
WO 2011/091513 discloses another crystalline form of Lubiprostone, i.e., APO-II, hereinafter referred to as Lubiprostone crystal III, which has an X-ray powder diffraction diffractogram as shown inFig. 4 and a differential scanning calorimetry thermogram comprising an endothermic peak with a peak onset temperature of approximately 76°C and a peak maximum of approximately 77°C. -
CN 104710398 discloses a further Lubiprostone crystal form, hereinafter referred to as Lubiprostone crystal IV, which has an X-ray powder diffraction pattern as shown inFig. 5 and a differential scanning calorimetry pattern comprising a peak maximum of 58±2°C. - Consequently, there is a demand for crystallization methods for the efficient and economical preparation of high-purity Lubiprostone crystals such that undesirable impurities, particularly impurity A, can be effectively reduced or avoided or can be easily removed during the crystallization purification method.
- Based on the above background, the inventors of the present invention carried out a series of research studies, and found to their surprise that the use of the solvents with high boiling points can obtain novel crystalline forms of Lubiprostone with high purity. The present invention relates, at least in part, to two crystalline forms of Lubiprostone, one form being precipitated from o-xylene or m-xylene and termed Lubiprostone crystal V, and the other form being precipitated from p-xylene and termed Lubiprostone crystal VI, and to methods for preparing the Lubiprostone crystal V and the Lubiprostone crystal VI.
- In one aspect, the present invention provides a method for preparing Lubiprostone crystal V, which comprises dissolving Lubiprostone in a first solvent selected from the group consisting of o-xylene, m-xylene, and a mixture thereof, to form a homogenous solution; lowering the temperature and/or adding to the homogenous solution a second solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof until a phase-separated fluid is formed at the bottom; pipetting out an upper clear solution and collecting the remaining phase-separated fluid; and evaporating off the phase-separated fluid under high vacuum until a precipitate is formed.
- In one aspect, the present invention provides another method for preparing Lubiprostone crystal V, which comprises dissolving Lubiprostone in a third solvent selected from the group consisting of o-xylene, m-xylene, ethyl ether, isopropyl ether, methyl tert-butyl ether, and mixtures thereof to form a homogenous solution; lowering the temperature and/or adding to the homogenous solution a fourth solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof; adding a seed crystal of Lubiprostone crystal V; and stirring until a precipitate is formed.
- In one aspect, the present invention provides a Lubiprostone crystal V having a X-ray powder diffraction (XRPD) pattern exhibiting its five strongest characteristic peaks at the following 2θ reflection angles: 6.5±0.2°, 13.2±0.2°, 15.6±0.2°, 18.9±0.2°, and 20.2±0.2°, wherein a half peak width of the characteristic peaks at 2θ reflection angles is between 0.3° and 2°.
- In one aspect, the present invention provides a method for preparing Lubiprostone crystal VI, which comprises dissolving Lubiprostone in p-xylene to form a homogenous solution; lowering the temperature and/or adding to the homogenous solution a solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof; and stirring until a precipitate is formed.
- In one aspect, the present invention provides a Lubiprostone crystal VI having an XRPD pattern exhibiting its five strongest intensity peaks at the following 2θ reflection angles: 7.5±0.2°, 10.3±0.2°, 13.9±0.2°, 18.7±0.2°, and 21.1±0.2°.
- In another aspect, the present invention provides novel Lubiprostone crystals useful for the production of high-purity Lubiprostone by crystallization.
-
-
Fig. 1 shows an X-ray powder diffraction (XRPD) pattern of Lubiprostone crystal I. -
Fig. 2 is an ideal X-ray powder diffraction (XRPD) pattern calculated from the single crystal data of Lubiprostone crystal II. -
Fig. 3 is another ideal X-ray powder diffraction (XRPD) pattern calculated from the single crystal data of Lubiprostone crystal II. -
Fig. 4 shows an X-ray powder diffraction (XRPD) pattern of Lubiprostone crystal III. -
Fig. 5 shows an X-ray powder diffraction (XRPD) pattern of Lubiprostone crystal IV. -
Fig. 6 shows an X-ray powder diffraction (XRPD) pattern of Lubiprostone crystal V. -
Fig. 7 shows a differential scanning calorimetry (DSC) thermogram pattern of Lubiprostone crystal V. -
Fig. 8 shows a Fourier Transform Infrared (FTIR) spectrum of Lubiprostone crystal V. -
Fig. 9 shows an X-ray powder diffraction (XRPD) pattern of Lubiprostone crystal VI. -
Fig. 10 shows a differential scanning calorimetry (DSC) thermogram of Lubiprostone crystal VI. -
Fig. 11 shows XRPD patterns of the Lubiprostone crystals which were prepared from the isopropyl acetate/heptane system at (a) 30°C, 18h, 100 rpm; (b) 25°C, 18h, 100 rpm; (c) 20°C, 18h, 100 rpm; (d) 10°C, 18h, 100 rpm; (e) 0°C, 18h, 100 rpm; (f) 20°C, 18h, 50 rpm; (g) 20°C, 18h, 200 rpm; and (h) 20°C, 18h, 250 rpm. -
Fig. 12 shows the crystal form transformation of Lubiprostone crystal V which was stirred in isopropyl acetate/heptane for (a) 20°C, 0 h; and (b) 20°C, 2 h. - In the present invention, the method for preparing Lubiprostone crystal V comprises the steps of:
- (a) dissolving crude Lubiprostone in a first solvent selected from the group consisting of o-xylene, m-xylene, and a mixture thereof to form a homogenous solution;
- (b) lowering the temperature and/or adding to the homogeneous solution a second solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof until a phase-separated fluid is formed at the bottom;
- (c) pipetting out an upper clear solution and collecting the remaining phase-separated fluid;
- (d) optionally adding a seed crystal of Lubiprostone crystal V;
- (e) evaporating off the phase-separated fluid under high vacuum until a precipitate is formed;
- (f) adding the second solvent to rinse the precipitate;
- (g) filtering out the precipitate, thereby isolating the Lubiprostone crystal V; and
- (h) optionally drying the Lubiprostone crystal V.
- The selection of the first solvent is the key to determine whether a crystalline form of Lubiprostone can be obtained and/or what kind of crystalline form of Lubiprostone is obtained. In the present invention, the first solvent used to dissolve the crude Lubiprostone is selected from the group consisting of o-xylene, m-xylene, and a mixture thereof, preferably o-xylene. The volume of the first solvent ranges from about 0.5 ml to about 10 ml, preferably about 1 ml to about 5 ml, and more preferably about 1.5 ml to about 4 ml, per 1 g of the crude Lubiprostone. The crude Lubiprostone can be dissolved in the first solvent at a temperature ranging from about 0°C to about 80°C, preferably from about 20°C to about 70°C, and more preferably from room temperature to about 60°C.
- In a preferred embodiment, the second solvent is selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof, and preferably n-pentane, n-hexane, cycloheptane, n-heptane, and mixtures thereof. The volume of the second solvent ranges from about 0.5 ml to about 30 ml, preferably about 1 ml to about 15 ml, and more preferably about 2 ml to about 10 ml, per 1 ml of the first solvent. The second solvent can be added at a temperature ranging from about -10°C to about 80°C, preferably from about -5°C to about 60°C, and more preferably from about 0°C to about 30°C.
- In one embodiment of the present invention, the temperature of the homogenous solution is lowered to a temperature ranging from about -10°C to about 40°C, preferably from about 0°C to about 30°C, and more preferably from about 10°C to about 25°C.
- In one embodiment of the present invention, the precipitation of the crystal can be performed at a temperature ranging from about -10°C to about 40°C, preferably about 0°C to about 30°C, and more preferably about 10°C to about 25°C.
- In one embodiment of the present invention, the step of evaporating off the phase-separated fluid can be performed under reduced pressure of about 10-4 Torr to about 25 Torr, preferably about 10-2 Torr to about 10 Torr, and preferably about 10-1 Torr to about 1 Torr.
- The aforementioned method can directly produce novel Lubiprostone crystal V, which is essentially a single crystalline form and does not contain any other crystalline forms of Lubiprostone, without the addition of any crystal seeds. The Lubiprostone crystal V thereby obtained can be used as crystal seeds for copying Lubiprostone crystal V.
- The present invention provides another process to copy Lubiprostone crystal V, which comprises the steps of:
- (a) dissolving Lubiprostone in a third solvent selected from the group consisting of o-xylene, m-xylene, ethyl ether, isopropyl ether, methyl tert-butyl ether, and mixtures thereof to form a homogenous solution;
- (b) lowering the temperature and/or adding a fourth solvent to the homogeneous solution selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof;
- (c) adding a seed crystal of Lubiprostone crystal V;
- (d) stirring until a precipitate is formed;
- (e) filtering out the precipitate, thereby isolating the Lubiprostone crystal V; and
- (f) optionally drying the Lubiprostone crystal V.
- In an embodiment of the present invention, the third solvent is selected from the group consisting of o-xylene, m-xylene, ethyl ether, isopropyl ether, methyl tert-butyl ether, and mixtures thereof, preferably isopropyl ether. The volume of the third solvent ranges from about 0.5 ml to about 10 ml, preferably about 1 ml to about 5 ml, and more preferably about 1.5 ml to about 4 ml, per 1 g of the crude Lubiprostone. The crude Lubiprostone can be dissolved in the third solvent at a temperature ranging from about 0°C to about 80°C, preferably from about 20°C to about 70°C, and more preferably from room temperature to about 60°C.
- In an embodiment of the present invention, the fourth solvent is selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and a mixture thereof, and preferably n-pentane, n-hexane, cycloheptane, n-heptane, and mixtures thereof. The volume of the fourth solvent ranges from about 0.5 ml to about 30 ml, preferably about 1 ml to about 15 ml, and more preferably about 2 ml to about 10 ml, per 1 ml of the third solvent. The fourth solvent can be added at a temperature ranging from about -50°C to about 80°C, preferably from about -10°C to about 60°C, and more preferably from about 0 to about 30°C.
- In one embodiment of the present invention, the temperature of the homogenous solution is lowered to a temperature ranging from about -30°C to about 40°C, preferably about -10°C to about 30°C, and more preferably about 10°C to about 25°C.
- The precipitation of crystal can be carried out at a temperature ranging from about -10°C to about 40°C, preferably about 0°C to about 30°C, and more preferably about 10°C to about 25°C.
- The step of filtering out the precipitate comprises using the fourth solvent or a mixture of the third solvent and the fourth solvent to wash the precipitate. The mixed solvent can contain portions of the third solvent and the fourth solvent in a ratio of about 1:1 to about 1:100, preferably about 1:1 to about 1:10.
- The third solvent is the key to determine whether the Lubiprostone crystal V can be directly copied using a seed of Lubiprostone crystal V. For example, the applicant found that when using esters such as isopropyl acetate as the third solvent, Lubiprostone crystal V is rapidly converted into Lubiprostone crystal I; thus, such solvent cannot be used to copy Lubiprostone crystal V. Even using a large amount of Lubiprostone crystal V as seed crystals, it is still impossible to obtain Lubiprostone crystal V. However, the inventors found to their surprise that using o-xylene, m-xylene, ethyl ether, isopropyl ether, or methyl tert-butyl ether as the third solvent renders the Lubiprostone crystal V very stable and highly unlikely to convert to Lubiprostone crystal I. Based on this method, high-purity Lubiprostone crystal V can be obtained in the presence of a seed crystal of Lubiprostone crystal V. If a crystal seed of Lubiprostone crystal V is not added, the method only produces either Lubiprostone crystal I or a mixture of Lubiprostone crystal I and Lubiprostone crystal V. Moreover, regardless of the amount of impurity A that is contained in the crystal seed of Lubiprostone crystal V or in the crude Lubiprostone, the resultant Lubiprostone crystal V is essentially free of impurity A. In other words, the crystallization method effectively removes impurity A from the crude Lubiprostone and the crystal seed of Lubiprostone.
- In one embodiment of the present invention, the Lubiprostone crystal V has an XRPD pattern exhibiting its five strongest characteristic peaks at the following 2θ reflection angles: 6.5±0.2°, 13.2±0.2°, 15.6±0.2°, 18.9±0.2°, and 20.2±0.2°. In a preferred embodiment, the XRPD pattern further comprises characteristic peaks at the following 2θ reflection angles: 10.8±0.2°, 14.0±0.2°, 14.8±0.2°, 16.0±0.2°, 17.8±0.2°, 21.0±0.2°, and 21.4±0.2°. More preferably, the XRPD pattern of Lubiprostone crystal V is consistent with
Fig. 6 . The particular data of Lubiprostone crystal V are shown in Table 1.Table 1 2θ angle (°) d value (Å) relative intensity (%) 6.5 13.6 100.0 9.4 9.4 5.5 10.8 8.2 14.6 11.6 7.6 7.8 13.2 6.7 45.4 14.0 6.3 17.5 14.8 6.0 24.8 15.6 5.7 68.0 16.0 5.5 48.5 17.8 5.0 42.4 18.9 4.7 93.4 20.2 4.4 50.5 21.0 4.2 43.9 21.4 4.2 43.9 21.7 4.1 31.1 22.2 4.0 20.9 23.0 3.9 17.1 24.2 3.7 19.8 24.8 3.6 16.2 25.5 3.5 16.1 27.1 3.3 15.0 27.5 3.2 15.2 28.4 3.1 15.5 29.1 3.1 16.8 29.6 3.0 15.2 30.0 3.0 14.2 31.1 2.9 13.8 32.6 2.7 12.7 34.9 2.6 11.5 35.4 2.5 11.8 37.1 2.4 11.8 37.8 2.4 12.0 38.6 2.3 11.2 40.1 2.2 11.1 41.3 2.2 11.7 44.3 2.0 9.7 45.9 2.0 8.5 - In one embodiment, the present invention provides a Lubiprostone crystal V having an XRPD pattern exhibiting its five strongest characteristic peaks at the following 2θ reflection angles: 6.5±0.2°, 13.2±0.2°, 15.6±0.2°, 18.9±0.2°, and 20.2±0.2°, wherein a half peak width of the characteristic peaks at 2θ reflection angles is between 0.3 and 2°.
- In one embodiment, the present invention provides a Lubiprostone crystal V having an XRPD pattern substantially as shown in
Fig 6 . - Lubiprostone crystal V obtained by the method of the present invention is essentially a single crystalline form, and thus does not contain any other crystalline forms, such as Lubiprostone crystal I. As shown in
Fig.6 , there is the only one characteristic peak at the 2θ reflection angles between 2° and 10°, i.e., at 6.5±0.2°, but not 7.6±0.2° (one characteristic peak of Lubiprostone crystal I). In a preferred embodiment, the present invention provides a Lubiprostone crystal V having an XRPD pattern exhibiting its five strongest characteristic peaks at the following 2θ reflection angles: 6.5±0.2°, 13.2±0.2°, 15.6±0.2°, 18.9±0.2°, and 20.2±0.2°, and substantially free of a characteristic peak at 2θ reflection angle of 7.6±0.2°. In the present invention, the term "substantially free of" means that in the XRPD pattern, the peak intensity at 7.6±0.2° is less than 5%, preferably less than 1% of the peak intensity at 6.5±0.2°. - In one embodiment, the present invention provides a Lubiprostone crystal V having a differential scanning calorimetry (DSC) thermogram pattern comprising an endothermic peak with a peak onset temperature of 60.6°±1°C and a peak maximum of 64.7±1°C.
- In one embodiment, the present invention provides a Lubiprostone crystal V having a DSC thermogram pattern substantially as shown in
Fig 7 . - In one embodiment, the present invention provides a Lubiprostone crystal V having a 1% KBr Fourier transform infrared (FTIR) spectrum comprising peaks, in terms of cm-1, at 3388±4, 2938±4, 2872±4, 1729±4, 1713±4, 1415±4, 1247±4, 1222±4, 1207±4, 1180±4, 1105±4, 1091±4, 1060±4, 1006±4, 987±4, 918±4, 761±4, and 723±4.
- In one embodiment, the present invention provides a Lubiprostone crystal V having a 1% KBr FTIR spectrum substantially as shown in
Fig. 8 . - The Lubiprostone crystal V of the present invention contains no more than about 0.3%, preferably no more than about 0.2%, preferably no more than about 0.1% of impurity A, and more preferably contains a non-detectable level of impurity A as determined by HPLC method, the detection limit of HPLC method being more than 0.02%.
- In addition, the Lubiprostone crystal V of the present invention shows good stability, with no other crystalline forms or degraded products of impurity A, even after six months of storage at normal temperatures for Lubiprostone (about -20°C).
- In one embodiment, the process for preparing Lubiprostone crystal VI comprises the steps of:
- (a) dissolving crude Lubiprostone in p-xylene to form a homogenous solution;
- (b) lowering the temperature and/or adding a fifth solvent to the homogenous solution selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof;
- (c) optionally adding a seed crystal of Lubiprostone crystal VI;
- (d) stirring the mixture until precipitation occurs thereby forming a precipitate;
- (e) filtering out the precipitate, thereby isolating the Lubiprostone crystal VI; and
- (f) optionally drying the Lubiprostone crystal VI.
- In one embodiment, the volume of p-xylene ranges from about 0.5 ml to about 10 ml, preferably about 1 ml to about 5 ml, and preferably about 1.5 ml to about 4 ml, per 1 g of the crude Lubiprostone. The crude Lubiprostone can be dissolved in p-xylene at a temperature ranging from about 10°C to about 80°C, preferably from about 20°C to about 70°C, and more preferably from about room temperature to about 60°C.
- In one embodiment, the fifth solvent is selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof, and preferably n-pentane, n-hexane, cycloheptane, n-heptane, and mixtures thereof. The volume of the fifth solvent ranges from about 0.5 ml to about 30 ml, preferably about 1 ml to about 15 ml, and preferably about 2 ml to about 10 ml, per 1 ml of p-xylene. This solvent can be added at a temperature ranging from about 10°C to about 80°C, preferably from about 15°C to about 60°C, and more preferably from about 20°C to about 50°C.
- In one embodiment of the present invention, the temperature of the homogenous solution is lowered to a temperature ranging from about 0°C to about 40°C, preferably from about 15°C to about 30°C, and more preferably from about 15°C to about 25°C.
- The precipitation of the crystal may be performed at a temperature ranging from about 10°C to about 40°C, preferably about 12°C to about 30°C, and more preferably about 15°C to about 25°C.
- The filtering out of the precipitate comprises using the fifth solvent or a mixture of p-xylene and the fifth solvent to wash the precipitate. In the mixed solvent, the quantities of p-xylene and the fifth solvent is in a ratio of about 1:1 to about 1:100, preferably about 1:1 to about 1:10.
- Lubiprostone crystal VI obtained by the aforementioned method of the present invention is essentially a single crystalline form, and contains a lower amount or even is substantially free of impurity A.
- In the present invention, Lubiprostone crystal VI has an XRPD pattern exhibiting its five strongest characteristic peaks at the following 2θ reflection angles: 7.5±0.2°, 10.3±0.2°, 13.9±0.2°, 18.7±0.2°, and 21.1±0.2°. More preferably, the XRPD pattern of Lubiprostone crystal VI is consistent with
Fig. 9 . The particular data of Lubiprostone crystal VI are shown in Table 2Table 2 2θ angle (°) d value (Å) relative intensity (%) 6.2 14.2 19.5 7.5 11.9 66.7 10.3 8.6 100.0 11.2 7.9 11.3 11.8 7.5 10.0 12.5 7.1 20.8 12.9 6.9 13.3 13.9 6.3 64.3 14.8 6.0 29.5 15.3 5.8 25.5 17.0 5.2 27.2 18.7 4.7 84.1 19.3 4.6 46.6 21.1 4.2 67.5 22.3 4.0 41.4 23.1 3.9 29.9 23.8 3.7 29.9 26.2 3.4 20.7 28.9 3.1 21.1 31.4 2.9 22.0 33.5 2.7 17.6 37.9 2.4 18.1 41.1 2.2 17.8 45.0 2.0 12.2 47.3 1.9 10.5 - In one embodiment, the present invention provides a Lubiprostone crystal VI having a DSC thermogram pattern comprising an endothermic peak with a peak onset temperature of approximately 47.4±1°C and a peak maximum of approximately 50.7±1°C. In a preferred embodiment, the present invention provides a Lubiprostone crystal VI having a DSC thermogram pattern substantially as shown in
Fig. 10 . - The Lubiprostone crystal VI of the present invention contains no more than about 0.3%, preferably no more than about 0.2%, preferably no more than about 0.1% of impurity A, and more preferably contains a non-detectable level of impurity A as determined by HPLC method, the detection limit of HPLC method being more than 0.02%.
- The following examples are used to further illustrate the present invention, but are not intended to limit the scope of the present invention.
- X-ray Powder Diffraction (XRPD) Analysis: The XRPD patterns were collected on a Bruker D2 PHASER diffractometer with fixed divergence slits and ID LYNXEYE detector. The samples (ca. 100 mg) were flatly placed on a sample holder. The prepared samples were analyzed over a 2θ range from 5° to 50° with step size of 0.02 degrees and step time of 1 second using CuKα radiation at a power of 10 mA and 30 kV. The CuKβ radiation was removed by a divergent beam nickel filter.
- Differential Scanning Calorimetry (DSC) Analysis: The DSC patterns were collected on a TA DISCOVERY DSC25 instrument. The samples (ca. 5 mg) were weighed into an aluminum pan with a crimping closed aluminum lid. The prepared samples were analyzed from 10°C to 100°C at scan rate of 10°C/min under a flow of nitrogen (ca. 50 ml/min). The melting point temperature and heat of fusion were calibrated by indium (In) before measurement.
- Fourier Transform Infrared (FTIR) Analysis: The FTIR spectra were collected on a
Perkin Elmer SPECTRUM 100 instrument. The samples were mixed with potassium bromide (KBr) in an approximately 1:100 ratio (w/w) using an agate mortar and pestle. The mixture was compressed in a pellet die at a pressure of about 10 to 13 tonnes for 2 minutes. The resulting disk was scanned 4 times against a collected background from 4000 cm-1 to 650 cm-1 at a resolution of 4 cm-1. The data was baseline corrected and normalized. - 4-Methoxybenzyl 7-[(2R, 4aR, 5R, 7aR)-2-(1,1-difluoro-pentyl)-octahydro-2-hydroxy -6-oxocyclopenta[b]pyran-5-yl)heptanoate (60 g, 117.5 mmol, enantiomeric purity ≥ 99%) was dissolved in 600 ml ethyl acetate and followed by addition of 5% palladium on charcoal under hydrogen for 3 hours. Then, the reaction mixture was filtered with celite pad. The solvent was evaporated off under vacuum. The crude product was purified by chromatography on silica gel using a mixture of hexane and ethyl acetate as a gradient eluent to obtain 40 g oily Lubiprostone. HPLC analysis of the product showed that 1.1% impurity A was found.
- Oily Lubiprostone (0.51 g, from Example 1) and p-xylene (1.0 ml) were heated at 40°C for dissolution and then cooled to room temperature. A solvent of n-pentane (1.0 ml) was added slowly dropwise and the mixture was stirred in an ice-water bath for 1 hour until solid precipitation occurred. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to give 0.38 g Lubiprostone crystal VI. HPLC analysis of the product showed that no impurity A was found. The XRPD and DSC results were as shown in
Fig. 9 and Fig. 10 . - Oily Lubiprostone (0.52 g, from Example 1) and p-xylene (1.3 ml) were heated at 40°C for dissolution and then cooled to room temperature. The mixture was stirred in an ice-water bath for 1 hour until solid precipitation occurred. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to give 0.41 g Lubiprostone crystal VI. HPLC analysis of the product showed that no impurity A was found. The XRPD and DSC results were the same as shown in
Fig. 9 and Fig. 10 . - Oily Lubiprostone (0.50 g, from Example 1) and p-xylene (1.0 ml) were heated at 40°C for dissolution and then cooled to room temperature. A solvent of n-pentane (1.0 ml) was added slowly dropwise and the mixture was stirred for 1 hour until solid precipitation occurred. Afterwards, the resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to give 0.41 g Lubiprostone crystal VI. HPLC analysis of the product showed that no impurity A was found. The XRPD and DSC results were the same as shown in
Fig. 9 and Fig. 10 . - Oily Lubiprostone (0.20 g, from Example 1) and p-xylene (1.0 ml) were heated at 40°C for dissolution and then cooled to room temperature. A solvent of n-hexane (1.0 ml) was added slowly dropwise and the mixture was stirred for 1 hour until solid precipitation occurred. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to 0.14 g give Lubiprostone crystal VI. HPLC analysis of the product showed that no impurity A was found. The XRPD and DSC results were the same as shown in
Fig. 9 and Fig. 10 . - Oily Lubiprostone (0.20 g, from Example 1) and o-xylene (0.5 ml) were heated at 40°C for dissolution and then cooled to room temperature. A solvent of n-pentane (1.0 ml) was added slowly dropwise and the mixture was stirred in ice water bath for 2 hours until a phase-separated fluid formed. The phase-separated fluid was then separated and evaporated under vacuum at ambient temperature until solid precipitation occurred. The resulting precipitate was washed with 1.0 ml n-pentane, and isolated by filtration and dried under vacuum at ambient temperature to give 0.10 g Lubiprostone crystal V. HPLC analysis of the product showed that 0.21% impurity A was found. The XRPD, DSC, and FTIR results were as shown in
Fig. 6 ,Fig. 7 and Fig. 8 . - Oily Lubiprostone (0.20 g, from Example 1) and o-xylene (0.5 ml) were heated at 40°C for dissolution and then cooled to room temperature. A solvent of n-pentane (1.0 ml) was added slowly dropwise and the mixture stirred for 2 hours until a phase-separated fluid formed. The phase-separated fluid was then separated and evaporated under vacuum at ambient temperature until solid precipitation occurred. The resulting precipitate was washed with 1.0 ml n-pentane, and isolated by filtration and dried under vacuum at ambient temperature to give 0.12 g Lubiprostone. The XRPD, DSC, and FTIR results were the same as shown in
Fig. 6 ,Fig. 7 and Fig. 8 . HPLC analysis of the product showed that 0.18% impurity A was found. - Oily Lubiprostone (0.20 g, from Example 1) and m-xylene (0.5 ml) were heated at 40°C for dissolution and then cooled to room temperature. A solvent of n-heptane (1.0 ml) was added slowly dropwise and stirred for half an hour until a phase-separated fluid formed. The phase-separated fluid was then separated and evaporated under vacuum at ambient temperature until solid precipitation occurred. The resulting precipitate was washed with 1.0 ml n-heptane, and isolated by filtration and dried under vacuum at ambient temperature to give 0.11 g Lubiprostone. The XRPD, DSC, and FTIR results were the same as shown in
Fig. 6 ,Fig. 7 and Fig. 8 . HPLC analysis of the product showed that 0.1% impurity A was found. - Oily Lubiprostone (0.50 g, from Example 1) and o-xylene (2.0 ml) were heated at 40°C for dissolution and then cooled to room temperature. A solvent of n-pentane (4.0 ml) was added slowly dropwise, and then seed crystal (10 mg, crystal V as prepared in Example 6) was added and the mixture was stirred for 1 hour until solid precipitation occurred. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for 4 hours to give Lubiprostone Crystal V (0.32 g). The XRPD, DSC, and FTIR results were the same as shown in
Fig. 6 ,Fig. 7 and Fig. 8 . HPLC analysis of the product showed that no impurity A was found. - Oily Lubiprostone (0.20 g, from Example 1) and isopropyl ether (0.6 ml) were heated at 40°C for dissolution and then cooled to room temperature. A solvent of n-heptane (0.6 ml) was added slowly dropwise, and then seed crystal (10 mg, crystal V as prepared in Example 6) was added and the mixture was stirred for 1 hour until solid precipitation occurred. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for half an hour to give Lubiprostone crystal V (0.11 g). The XRPD, DSC, and FTIR results were the same as shown in
Fig. 6 ,Fig. 7 and Fig. 8 . HPLC analysis of the product showed that no impurity A was found. - Oily Lubiprostone (0.20 g, from Example 1) and methyl tert-butyl ether (0.6 ml) were heated at 40°C for dissolution and then cooled to room temperature. A solvent of n-pentane (0.6 ml) was added slowly dropwise, and then seed crystal (10 mg, crystal V as prepared in Example 6) was added and the mixture was stirred for 1 hour until solid precipitation occurred. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for half an hour to give Lubiprostone crystal V (0.10 g). The XRPD, DSC, and FTIR results were the same as shown in
Fig. 6 ,Fig. 7 and Fig. 8 . HPLC analysis of the product showed that no impurity A was found. - Oily Lubiprostone (0.20 g, from Example 1) and ethyl ether (0.6 ml) were heated at 40°C for dissolution and then cooled to room temperature. A solvent of n-hexane (0.8 ml) was added slowly dropwise, and then seed crystal (10 mg, crystal V as prepared in Example 6) was added and the mixture was stirred for 1 hour until solid precipitation occurred. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature for half an hour to give Lubiprostone crystal V (0.14 g). The XRPD, DSC, and FTIR results were the same as shown in
Fig. 6 ,Fig. 7 and Fig. 8 . HPLC analysis of the product showed that no impurity A was found. - Oily Lubiprostone (0.20 g, from Example 1, enantiomeric purity > 99%) and isopropyl acetate (0.16 ml, 0.8 parts) were heated at 40°C for dissolution and then cooled to 30°C, 25°C, 20°C, 10°C, and 0°C, respectively. Heptane (0.84 ml, 4.2 parts) was added slowly dropwise, and the mixture was stirred (at 50, 100, 200, or 250 rpm) for 18 hours until solid precipitation occurred at 30°C, 25°C, 20°C, 10°C, and 0°C, respectively. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature to give Lubiprostone crystal II. The XRPD results are shown in
Figs. 11(a) to 11(h). - As shown in
Figs. 11(a) to 11(h), only the patterns depicted inFig. 1 andFig. 3 (Lubiprostone crystal I), but not the pattern depicted inFig. 2 , can be seen in the XRPD patterns ofFigs. 11(a) to 11(h) . The results demonstrate thatFig. 1 andFig. 3 (i.e.,Fig. 3 ofUS 2010/056808 ) show the XRPD patterns of the crystalline forms of Lubiprostone, andFig. 2 (i.e.,Fig. 2 ofUS 2010/056808 ) shows the XRPD pattern of an enantiomorph of Lubiprostone. This is because the oil Lubiprostone used in this example only contains less than 1% enantiomer, which is lower than the detection limit of the XRPD analysis, so the pattern of the enantiomorph of Lubiprostone cannot be seen in all of the XRPD patterns. Given this,Fig. 2 ofUS 2010/0056808 shows the XRPD pattern of the enantiomorph of Lubiprostone, rather than the crystalline form of Lubiprostone. - Therefore, although the XRPD pattern of Lubiprostone crystal V shown in
Fig. 6 is similar to that inFig. 2 , the polymorph A shown inFig. 2 ofUS 2010/056808 is an enantiomorph of Lubiprostone, rather than Lubiprostone crystal V which is a single crystalline form. In addition, it can be seen that a major difference between the patterns shown inFig. 2 andFig. 6 is the half peak width of the characteristic peaks at 2θ reflection angles. The half peak width of Lubiprostone crystal V at 2θ reflection angles is between about 0.3° and about 2°, but the half peak width shown inFig. 2 at 2 θ reflection angles is below 0.3°, which means that the average crystal sizes of the Lubiprostone crystal V and the enantiomorph of Lubiprostone are different. - Lubiprostone crystal V (0.20 g, from Example 9) was added to a mixture of isopropyl acetate (0.16 ml) and heptane (0.84 ml)(i.e., the solvent system for crystallization of
US 2010/056808 ), and the mixture was stirred at 20°C for 2 hours. The resulting suspension was filtered and rinsed, and then dried under high vacuum at room temperature to give Lubiprostone crystal I. The XRPD results are shown inFigs. 12(a) and 12(b) . - As shown in
Figs. 12(a) and 12(b) , the crystalline form of Lubiprostone crystal V has been completely converted to the crystalline form shown inFig. 1 andFig. 3 (Lubiprostone crystal I) within only two hours. The results prove that Lubiprostone crystal II obtained fromUS 2010/056808 does not contain any Lubiprostone crystal V because Lubiprostone crystal V cannot be present under the crystallization conditions ofUS 2010/056808 over 18 hours. Therefore, the Lubiprostone crystal V is a novel crystalline form of Lubiprostone, and the crystalline form shown inFig. 2 found in the unit cell of Lubiprostone crystal II by optical microscope is an enantiomorph of Lubiprostone, rather than Lubiprostone crystal V.
Claims (15)
- A Lubiprostone crystal VI having an X-ray powder diffraction (XRPD) pattern exhibiting its five strongest characteristic peaks at the following 2θ reflection angles: 7.5±0.2°, 10.3±0.2°, 13.9±0.2°, 18.7±0.2°, and 21.1±0.2°.
- The Lubiprostone crystal VI of claim 1, wherein(i) the XRPD pattern further comprises characteristic peaks at the following 2θ reflection angles: 6.2±0.2°, 12.5±0.2°, 14.8±0.2°, 15.3±0.2°, 17.0±0.2°, 19.3±0.2°, 22.3±0.2°, 23.8±0.2°, and 26.2±0.2°; and/or(ii) the XRPD pattern is substantially shown in Fig. 9.
- The Lubiprostone crystal VI of claim 1 further having(i) a differential scanning calorimetry (DSC) thermogram pattern comprising an endothermic peak with a peak onset temperature of 47.4±1°C and a peak maximum of 50.7±1°C; and/or(i) a differential scanning calorimetry (DSC) thermogram pattern being substantially shown in Fig. 10.
- A method for preparing the Lubiprostone crystal VI of any of claims 1 to 3, which comprises the steps of:dissolving Lubiprostone in p-xylene to form a homogenous solution;lowering the temperature and/or adding a solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof; andstirring until a precipitate is formed.
- The method of claim 4, further comprising the step of adding a seed crystal of Lubiprostone crystal VI, prior to the stirring step.
- The method of claim 5, further comprising the steps of:filtering out the precipitate, thereby isolating the Lubiprostone crystal VI; andoptionally drying the Lubiprostone crystal VI.
- A Lubiprostone crystal V having an X-ray powder diffraction (XRPD) pattern exhibiting its five strongest characteristic peaks at the following 2θ reflection angles: 6.5±0.2°, 13.2±0.2°, 15.6±0.2°, 18.9±0.2°, and 20.2±0.2°, wherein a half peak width of the characteristic peaks at 2θ reflection angles is between 0.3° and 2°.
- The Lubiprostone crystal V of claim 7, wherein:(i) the XRPD pattern is substantially free of a characteristic peak at 2θ reflection angle of 7.6±0.2°; and/or(ii) the XRPD pattern is substantially shown in Fig. 6.
- The Lubiprostone crystal V of claim 7 further having(i) a differential scanning calorimetry (DSC) thermogram pattern comprising an endothermic peak with a peak onset temperature of 60.6±1°C and a peak maximum of 64.7±1°C; and/or(ii) a differential scanning calorimetry (DSC) thermogram pattern being substantially shown in Fig. 7.
- The Lubiprostone crystal V of claim 7 further having(i) a 1% KBr Fourier transform infrared (FTIR) spectrum comprising peaks, in terms of cm-1, at 3388±4, 2938±4, 2872±4, 1729±4, 1713±4, 1415±4, 1247±4, 1222±4, 1207±4, 1180±4, 1105±4, 1091±4, 1060±4, 1006±4, 987±4, 918±4, 761±4, and 723±4; and/or(ii) a 1% KBr Fourier transform infrared (FTIR) spectrum being substantially shown in Fig. 8.
- A method for preparing the Lubiprostone crystal V of any of claims 7 to 10, which comprises the steps of:dissolving Lubiprostone in a first solvent selected from the group consisting of o-xylene, m-xylene, and a mixture thereof to form a homogenous solution;lowering the temperature and/or adding to the homogeneous solution a second solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof until a phase-separated fluid is formed at the bottom;pipetting out an upper clear solution and collecting the remaining phase-separated fluid; andevaporating off the phase-separated fluid under high vacuum until a precipitate is formed.
- The method of claim 11, further comprising the step of optionally adding a seed crystal of Lubiprostone crystal V between the pipetting step and the evaporation step.
- The method of claim 11, further comprising the steps of:adding the second solvent for rinsing the precipitate;filtering out the precipitate, thereby isolating the Lubiprostone crystal V; andoptionally drying the Lubiprostone crystal V.
- A method for preparing the Lubiprostone crystal V of any of claims 7 to 10, which comprises the steps of:dissolving Lubiprostone in a third solvent selected from the group consisting of o-xylene, m-xylene, ethyl ether, isopropyl ether, methyl tert-butyl ether, and mixtures thereof to form a homogenous solution;lowering the temperature and/or adding a fourth solvent selected from the group consisting of pentane, hexane, heptane, octane, nonane, decane, cyclopentane, cyclohexane, cycloheptane, and mixtures thereof;adding a seed crystal of Lubiprostone crystal V; andstirring until a precipitate is formed.
- The method of claim 14, further comprising the steps of:filtering out the precipitate, thereby isolating the Lubiprostone crystal V; andoptionally drying the Lubiprostone crystal V.
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US16/034,686 US10253011B1 (en) | 2018-07-13 | 2018-07-13 | Lubiprostone crystals and methods for preparing the same |
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HUE034571T2 (en) * | 2006-02-07 | 2018-02-28 | Sucampo Pharma Llc | Method for preparing prostaglandin derivative |
CN101318948B (en) * | 2008-04-01 | 2011-04-27 | 上海天伟生物制药有限公司 | Lubiprostone1 crystal, preparation method and uses thereof |
CA2639240A1 (en) * | 2008-08-29 | 2010-02-28 | Alphora Research Inc. | Prostaglandin synthesis and intermediates for use therein |
US8513441B2 (en) | 2008-08-29 | 2013-08-20 | Alphora Research Inc. | Prostaglandin synthesis and intermediates for use therein |
CA2750487A1 (en) * | 2009-01-22 | 2010-07-29 | Apotex Pharmachem Inc. | Methods of making lubiprostone and intermediates thereof |
CN102020625B (en) * | 2009-09-22 | 2013-04-17 | 上海天伟生物制药有限公司 | High-purity lubiprostone, preparation method and application thereof |
WO2011072383A1 (en) * | 2009-12-18 | 2011-06-23 | Apotex Pharmachem Inc. | Processes for the purification of lubiprostone |
WO2011091513A1 (en) | 2010-01-28 | 2011-08-04 | Apotex Pharmachem Inc. | Polymorphic forms of lubiprostone |
NZ608823A (en) * | 2010-10-15 | 2014-11-28 | Scinopharm Kunshan Biochemical Technology Co Ltd | Processes for preparation of lubiprostone |
US20130184476A1 (en) * | 2011-07-13 | 2013-07-18 | Mark Jackson | Preparation of lubiprostone |
CN103787942B (en) * | 2012-11-02 | 2017-02-15 | 上海源力生物技术有限公司 | Intermediate for preparing lubiprostone, preparation method of intermediate and method for preparing lubiprostone through intermediate |
CN104140410B (en) * | 2013-05-09 | 2017-12-15 | 江苏豪森药业集团有限公司 | The preparation method of Lubiprostone 1 |
CA2925927C (en) * | 2013-09-30 | 2022-09-06 | George Petros Yiannikouros | Novel synthesis routes for prostaglandins and prostaglandin intermediates using metathesis |
CN105254657B (en) * | 2014-07-10 | 2018-06-15 | 台湾神隆股份有限公司 | Metal catalytic asymmetry 1,4- conjugate addition reactions generate prostaglandin and prostaglandin analogue |
KR20160070457A (en) * | 2014-12-10 | 2016-06-20 | 연성정밀화학(주) | Process for Preparing Lubiprostone and Intermediate Therefor |
KR20160070460A (en) * | 2014-12-10 | 2016-06-20 | 연성정밀화학(주) | Process for Purifying Lubiprostone |
US20180016230A1 (en) * | 2014-12-10 | 2018-01-18 | Apotex Inc. | Salts of Prostaglandin Analog Intermediates |
JP2015120693A (en) * | 2014-12-19 | 2015-07-02 | サイノファーム (クンシャン) バイオケミカル テクノロジ カンパニー リミテッド | Processes for preparation of lubiprostone |
CN104557845B (en) * | 2015-01-13 | 2020-12-22 | 齐鲁制药有限公司 | Preparation method of lubiprostone compound |
CN104710398A (en) * | 2015-02-17 | 2015-06-17 | 齐鲁制药有限公司 | Novel crystal form of lubiprostone and preparation method of crystal form |
CN104710298B (en) | 2015-03-10 | 2016-08-24 | 华东理工大学 | A kind of highly polar mixed solvent and application thereof |
CN107474033A (en) * | 2016-06-07 | 2017-12-15 | 北京深蓝海生物医药科技有限公司 | A kind of method of refined Lubiprostone 1 |
CN108503619A (en) * | 2017-02-23 | 2018-09-07 | 广州楷模生物科技有限公司 | The synthetic method of 1R, 2R, 3R- substituted cyclopentanone class compound |
US10457623B1 (en) * | 2018-07-13 | 2019-10-29 | Chirogate International Inc. | Process for the preparation of Lubiprostone and intermediates thereof |
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